Hypoxic Pulmonary Vasoconstriction May Be Stronger in Older Persons

The influence of age on the development of high altitude pulmonary edema (HAPE) has never been studied in a rigorous manner, but surveys of HAPE occurrence in alpine regions note a greater incidence in younger persons and men. Of several risk factors for HAPE, exaggerated hypoxic pulmonary vasoconstriction (HPV) is the single most predictive. Two recent studies interestingly find for the first time that older men (age >50) have stronger HPV than younger men (age <25) as assessed by echocardiographic measurement of pulmonary artery systolic pressure (PASP) in isocapnic normobaric hypoxia (Balanos et al., 2015) and poikilocapnic hypobaric hypoxia (Turner et al., 2015). In the isocapnic study by Balanos et al., the difference between the young and elderly was a 55% vs. 39% rise in PASP (15.2 vs. 9.8 mmHg), while in the poikilopcapnic study by Turner et al., the rise in PASP was roughly 60% less, indicative of the opposing influence of hypocapnia on the strength of HPV. There were no differences in cardiac output with hypoxia between the two age groups to explain the higher PASP responses in the older group. Aging is known to increase left ventricular diastolic stiffness in the elderly, and this contribution to the elevation in PASP was not determined in either study. Thus given these data, the lower apparent prevalence of HAPE in older persons cannot be ascribed to differences in HPV or pulmonary vascular reactivity as assessed by echocardiographically measured PASP.

Felines Native to High Altitude Do Not Have Hemoglobins with High Affinity for Oxygen

Cats are famously indifferent and independent. Most high altitude mammals and birds have evolved hemoglobins with high oxygen affinity. This strategy at high altitude leads to better oxygen delivery overall by gaining more in terms of oxygen uptake in the lungs than is lost with a lower facility to release oxygen in the tissue capillaries. However, as Janecka et al. (2015) report, the snow leopard (Panthera uncia) whose altitudinal range is as high as 6000 m in the Himalayas does not conform to this general pattern. Purified hemoglobin from this species exhibit a low O₂ affinity and a low sensitivity to 2,3-DPG, common to all feline species and thought to be a reason why cats generally do not do well at high altitude. Both these properties are attributable to a single amino acid substitution in the beta chain at a position where histidine is substituted by a phenylalanine. This substitution dates back to the earliest ancestor of the Felidae. How snow leopards survive at high altitude without altering their hemoglobin oxygen affinity and what mechanisms compensate will be interesting to explore in this ‘experiment of nature’. Will the compensation (s) be found in greater ventilation or cardiac output, or at the cellular level in terms of diffusion and mitochondrial oxygen utilization?

Intravenous Iron Supplementation Does Not Prevent or Decrease Acute Mountain Sickness

Iron is a necessary metal for countless metalloproteins, including those involved in hypoxia inducible factor (HIF) metabolism. Iron deficiency impairs the function of several prolyl hydroxylases that participate in oxygen sensing by negatively regulating HIF concentrations. Thus in iron deficiency, HIF may not be properly maintained at appropriate levels. One important response to high altitude and hypoxia is hypoxic pulmonary vasoconstriction (HPV), in which iron supplementation even in iron-replete subjects reduces HPV (Smith et al., 2009) and might conceivably reduce high altitude pulmonary edema. Whether the more common problem of acute mountain sickness might be prevented by iron via modulation of HIF activity is an interesting question. An earlier study by the same group that showed reduced HPV with iron supplementation found that iron infusion in 12 subjects may decrease AMS in a rapid ascent to 4350 m when compared to a placebo group (Talbot et al., 2011). Although there was no difference in scores qualifying for clinically important AMS (Lake Louise score >3), average subjects given iron had slightly lower scores and there was an inverse relationship between ferritin concentrations and AMS scores. Ren et al. (2015) report a second study of the issue in Chinese subjects flown from sea level to Lhasa, Tibet (4300 m). Using a similar dose of intravenous iron sucrose (200 mg), they found no statistically significant difference in AMS severity versus the control subjects given an intravenous placebo solution, although a trend was evident. In both studies, there was a significant rise in serum ferritin consistent with successful iron administration and augmentation of stores. In this slightly larger study of 19 subjects given iron (vs. 12 in the study by Talbot), there were no trends in improvement of oxygenation, heart rate, or blood pressure. Thus presently, while there is a suggestion of some small benefit in AMS prevention, intravenous iron, a very expensive intervention not without some risk, cannot be recommended until significantly larger placebo-controlled randomized studies are conducted and found definitive.

More on the Strategy of Bar-Headed Geese as They Fly over the Himalayas

Much work has been done in elucidating how bar-headed geese accomplish their overflight migrations of the Himalayas. The physiological basis for their astounding high altitude prowess include changes in their cerebral and pulmonary vasculature, alveolar diffusion, and hemoglobin O₂ affinity, to name but just a few. These findings have largely rested on altitude simulations on captive birds, but more recently technology has permitted ‘in flight’ monitoring of migrating geese's geographic position, altitude, heart rate, and wingbeat frequencies (a surrogate for energy expenditure), temperature, barometric pressure, and wind directional speeds. Utilizing such information, Bishop et al. (2015) show us how efficient at conserving energy these birds are in minimizing the costs of flying over the mountains. For instance, flying at high altitude is not as efficient as might be suggested by a lower air density due to the decline of aerodynamic lift. The flight profile of migrating birds is best described as a ‘roller coaster’ strategy, whereby geese track the underlying terrain and discard large altitude gains, only to recoup them later in the flight when they can take advantage of orographic lift.

Endothelin Receptor B May Be a Candidate Gene for High Altitude Adaptation

In a recent whole genome analysis of Ethiopian highlanders, Upda et al. (2014) identified a 208 kB gene-rich region on chromosome 19 with a significant loss of diversity, indicative of a selective sweep suggesting evolutionary pressure. One of the genes identified was for the endothelin receptor B (EDNRB), which is expressed throughout the cardiovascular system. To better understand the significance of this gene, Stobdan et al. (2015) developed mice heterozygous for the EdnrB gene and studied their cardiovascular performance in hypoxia. They found no significant differences in mild hypoxia (15% oxygen), but the heterozygous-deficient mice tolerated very severe hypoxia (5% oxygen) quite well in comparison to wild-type mice. Specifically, they had less hypotension, higher cardiac output, stronger myocardial contractility, lower plasma lactate concentrations, and higher brain, heart, and kidney tissue oxygen concentrations. These data demonstrate that a lower level of EDNRB expression significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Transcriptomic profiling of left ventricles revealed three specific genes (natriuretic peptide type A, sarcolipin, and myosin light polypeptide 4) that were oppositely expressed between heterozygotes and wild-type mice. Functions related to these gene networks were consistent with better cardiac contractility and performance. Although the heart tolerates hypoxia better than most organs and 5% oxygen is not a level of ambient hypoxia ever experienced by humans at altitude, these findings in mice suggest perhaps under high metabolic stress such as exercise at less profound altitudes, a variant of the gene for EDNRB with lesser responsiveness to endothelin may have afforded an evolutionary advantage. What remains to be determined is whether the gene in Ethiopian highlanders transcribes a receptor with lesser affinity for endothelin or decreased tissue expression.

Metalloproteinases Impair Blood Brain Barrier (BBB) Integrity in Hypoxia

Proteins with metalloproteinase activity are intimately involved with regulation of capillary permeability by their ability to break down proteins such as claudin-5 and others that maintain tight gap junctions. Hypoxia increases BBB permeability and this may in some individuals contribute to the development of AMS. To study the role of two metalloproteinases, ADAM (a disintegrin and metalloproteinase) 12 and 17 in hypoxia-mediated impairment of neural vascular barrier function, Cui et al. (2015) exposed mouse brain microvascular endothelial cell monolayers to 1% oxygen. As a result, the monolayers became leaky and displayed a loss of claudin-5 localization at gap junctions. These changes were completely suppressed by inhibition of ADAM 12 and 17 by specific siRNAs for these proteins. Mice then were exposed to 4%–7% oxygen for 36 hours. The retinas (as a surrogate for the BBB) were examined and found to accumulate an intravenously administered fluorescent probe. Claudin-5 expression in the hypoxic retinas was decreased. When ADAM 12 and 17 siRNAs were given prophylactically to the mice, these changes were hypoxia were prevented. These results suggest that AMS and high altitude cerebral edema might be prevented with inhibitors of these ADAMs if they play the same role in the human brain circulation.

Polymorphisms and Epigenetic Modifications in the Apelin System Are Associated with Susceptibility to HAPE

HAPE is associated with a reduced NO concentrations in exhaled air or bronchoalveolar lavage, and HAPE-susceptible individuals show endothelial dysfunction in the systemic circulation. Hypoxia inducible factor stimulates the expression of apelin, a potent vasodilator, which increases NO release by activation of endothelial NO synthase. Mishra et al. (2015) conducted a genome-wide association study in 200 subjects with HAPE at 3500 m, in 200 subjects without HAPE at a comparable altitude, and in 200 high altitude residents. They found polymorphisms in the genes of apelin and its receptor and greater methylation as an epigenetic regulation. These were, in combination or alone, associated with higher systolic pulmonary artery pressures, lower levels of apelin and nitrite (a marker of NO bioavailability) in subjects presenting with HAPE in contrast to the two control populations showing an opposite trend. The effects were, however, small and accounted for at most 5% of the variability of pulmonary artery pressure in these groups. The study suggests that genetic variation and epigenetic modifications of the apelin system can contribute to the multi-genic phenotype of HAPE susceptibility.

Minocycline, a Second Generation Tetracycline, Ameliorates Blood Brain Barrier Damage in Rats Acutely Exposed to 8000 M

Minocycline is known to have neuroprotective effects in cerebral trauma or hemorrhage, and spinal cord injury. Yang et al. (2015) investigated the effect of this drug on the blood brain barrier (BBB) in hypoxia in vitro (cell cultures at 1% O₂) and in vivo (rats exposed for 24 h to a simulated altitude of 8000 m). By Evans Blue staining and by electron microscopy they demonstrate that minocycline preserves the BBB integrity in hypoxia in vivo and in vitro, and they show that this effect can be attributed to the inhibition of the HIF-1α -mediated cellular response. If these effects occur also in humans at a degree of hypoxia associated with mountaineering, minocycline might protect against high altitude cerebral edema and be helpful for investigating whether a leak of the BBB is involved in the pathophysiology of acute mountain sickness.

Changes in Aerobic Capacity and HVR at 3450 M Correlate Between Fathers and Their Children

Kriemler et al. (2015) performed cardiopulmonary exercise testing (CEPT) in prepubertal children (9–12 years) and their fathers at low and high altitude. The study subjects were not altitude-acclimatized and were transported to high altitude in 2 hours by train. CEPT was performed at 450 m, 7 hours after arrival at 3450 m, and on the following 2 days. As expected, HVR increased significantly over time at altitude and VO₂peak declined by about 25 %, both in children and adults alike. Interestingly, maximal heart rate did not decline in children at high altitude and could apparently not be attributed to different levels of exhaustion. Explanations for the different behavior of maximal heart rate between adults and children remain speculative due to the completely noninvasive data collection in children. There were rather high correlations between fathers and children for the increase in HVR and the decrease of VO₂peak explaining 37% and 48% of the variability, respectively, by familial relations. These correlations may point to a hereditary component but behavioral factors such as the level of physical activity within families cannot be excluded.

Microhemorrhages in the Corpus Callosum Can Also Occur with Respiratory Failure at Low Altitude

Hemosiderin depositions due to microhemorrhages (MH) in the brain, predominantly located in the corpus callosum, can be found in most of the survivors of high altitude cerebral edema (HACE) but are rarely found after AMS or mountaineering to extreme altitude without supplemental oxygen. MH are detectable by susceptibility weighted MRI and they remain in the brain as a footprint of HACE. Riech et al. (2015) found MH predominantly in the corpus callosum in 3 patients who had never been exposed to very high altitudes but who had survived ARDS, two of whom were treated with extracorporeal membrane oxygenation (ECMO). The article cites other case reports of MH in the corpus callosum occurring at low altitude in two patients after EMCO during H1N1 infection, in one patient under long-term ventilation because of severe COPD, and in one patient after morphine poisoning. These case reports demonstrate that hemosiderin depositions in the brain similar to those found after HACE can occur at low altitude after severe respiratory failure. Arterial PO₂ did not fall much below 50 mmHg in these patients. Thus, it was considerably higher than during most cases of HACE. Therefore, it is likely that additional factors associated with the specific illnesses or treatments contributed to leaking of red cells through the blood brain barrier (BBB), such as inflammation increasing leakiness of the BBB or increased intravascular pressure due to impaired venous return or high cerebral blood flow with hypoxia and CO₂ retention.

Speckle Tracking Echocardiography Suggests “Subclinical” Endocardial Left Ventricular Dysfunction in Healthy Trekkers at 5400 M

The American Medical Expedition to Mt. Everest (AMREE) and Operation Everest II had shown normal or increased left ventricular (LV) function, no signs of ischemia in the ECG and no arrhythmias except for intermittent right bundle branch block up to an altitude of 7600 m in healthy individuals without supplemental oxygen. The latter finding and a rotation of the QRS axis to the right are explained by the considerable increase of pulmonary artery pressure at these altitudes. Speckle tracking echocardiography performed during the HIGH CARE STUDY on Mt. Everest demonstrates, however, an increase of the left ventricular twist (LVT) and torsion to shortening ratio in healthy trekkers at 5400 m (Osculati et al., 2015). Both parameters allow assessing predominantly the function of the subendocardial myocardium, which is most sensitive to inadequate oxygen supply. Volume reduction of the heart and hypoxia were the major determinants of the LVT increase, suggesting subendocardial systolic dysfunction. This is masked, however, by a compensating epicardium, resulting in unchanged or even increased global LV function as reported in the earlier studies mentioned above.

Intermittent Normobaric Hypoxia Corresponding to Altitudes of 3500 M and 4500 M Does Not Reduce Body Weight in Obese Patients

It is well established that a substantial loss of fat and lean body mass occur above an altitude of 5000 m, predominantly due to loss of appetite in the presence of increased energy requirements. Energy deficits at 8000 m are as high as 1700 kCal per day. Below 5000 m several studies had shown that body weight can be maintained over several weeks when an increased intake compensates the greater requirements due to the increased basic metabolic rate. Thus, reduction of appetite and increase of energy requirements is the rationale of adding exposure to hypoxia to weight loss programs. Gatterer et al. (2015) tested this hypothesis in a placebo-controlled, single blind study on 65 subjects with an average BMI of about 36. Participants had two sessions per week during which they exercised for 90 min at 50% VO₂max (68% maximal heart rate) at 14% O₂ (3500 m), or normoxia and thereafter rested for another 90 min at 12.2% (4500 m), or normoxia. There was no effect of hypoxic exposure as body weight decreased in both groups by 3 kg after 3 months and remained stable thereafter. The dropout rate of 52% is comparable to those of other interventional studies involving life style changes with and without exercise. Thus, adding hypoxic exposures at a dose that is tolerable for obese patients does not offer any advantage for weight loss programs.

Hemoglobin Mass Increases with Living and Training over Three Weeks at an Altitude of 1800 M

Recommendations for increasing total hemoglobin mass by 3%–5% with altitude exposure are a minimal exposure of 14 hours per day, a minimal altitude of 2100 m, and a minimal duration of 3 weeks. Others have calculated that hemoglobin mass increases by 1% for every 100 h spent above 2300 m. These recommendations considered 2100–2300 m as a threshold altitude for onset of erythropoiesis relevant for improvement of endurance performance. The study of Gavrican-Lewis et al. (2015) challenges this threshold concept in a small study. 16 elite or well-trained runners, all in pre-competition phase with similar training programs, lived and trained at 1800 m or at 640 m. Hemoglobin mass measured by CO-rebreathing increased at 1800 m by 3% after 2 weeks and did not increase further during the next week, while the corresponding values at low altitude were +0.4% and −1.1%. Unfortunately, logistic reasons precluded assessment of performance in these two groups. The study suggests that the threshold altitude for stimulation of erythropoiesis relevant to endurance athletes is at 1800 m or lower.